Primary cytomegalovirus (CMV) infections or those resulting from reactivation of latent virus causes severe morbidity and mortality in the immunocompromised host, including bone marrow transplant recipients inflicted with various forms of leukemia. Monocyte/macrophage tropism is central to CMV pathogenesis because this cell type disseminates virus, supports productive infection, and harbors latent CMV DNA. Unique CMV-macrophage interactions have evolved to preserve this relationship and guarantee survival of the virus within the host. The long-term goal of this project is to identify the function of CMV gene products that regulate monocyte/macrophage tropism. Using the mouse model of CMV pathogenesis, two US22 family members genes, M140 and M141, have been identified as determinants of macrophage tropism. The products of these two genes (pM140 and pM141) form a complex within the infected cell, and deletion of either gene attenuates growth of murine CMV (MCMV) in macrophages and the macrophage-rich environment of the spleen. The hypothesis of the proposed research is that pM140 functions both independently and as a defined, structural complex with pM141 to regulate downstream events in MCMV replication critical for efficient growth of the virus in the cellular environment of the macrophage. The specific objectives of this proposal are to 1) characterize the pM140/ pM141 complex with respect to structural components and stoichiometry, 2) identify the protein domains that facilitate pM140and pM141 complex formation, 3) determine the role of pM140 and the pM140/pM141 complex in MCMV pathogenesis, and 4) identify the molecular mechanisms of how these proteins function to confer macrophage tropism. Understanding the mechanisms of how MCMV replication is regulated in macrophages is crucial to understanding a key step in viral pathogenesis. The ability to manipulate replication of CMV in this cell type would afford opportunities to control the diseases that often manifest as a consequence of acute or reactivated CMV infections. [unreadable] [unreadable] [unreadable] [unreadable]